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Advanced Gastric Cancer

CE / CME

Cases and Challenges in the Optimal Treatment of Advanced Gastric Cancer

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit

Released: April 27, 2023

Expiration: April 26, 2024

Steven Maron
Steven Maron, MD
CME/CE Information

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Managing Toxicities of ICIs

Although treatment with ICIs is generally better tolerated than chemotherapy, it is associated with unique immune-related adverse events (IRAE)irAEs that are unpredictable and can affect almost any part of the body.14 In practice, irAEs predominantly manifest as GI (colitis), dermatologic (rash), endocrine (hypothyroidism), and pulmonary (pneumonitis) toxicities.15 Unfortunately, there is still no reliable way to predict which patients will develop an irAE or how severe a reaction will occur. 

IrAEs also differ from adverse effects of chemotherapy in that they can occur at any time during treatment, and even up to 2 years after ICI completion. Data from a real-world pharmacovigilance study suggests that the key period for development is approximately 40 days after ICI initiation.16,17 Early-onset irAEs often are related to epithelial inflammation and manifest as rash, colitis, or pneumonitis, whereas later onset reactions tend to be localized or organ-specific (Table 3).15,18-21 Fortunately, most irAEs are mild to moderate in severity and can be managed while patients safely continue treatment.17 Some irAEs that occur less frequently but can be severe include hyperglycemia, adrenal insufficiency, myocarditis, and hypophysitis.16 Others can be easy to miss or attributed to other causes, such as mucositis or arthralgia, and clinicians must maintain a high level of suspicion for irAEs in patients at all times.17

Table 3: Frequent irAEs With ICIs15,19-21

Patients with advanced GC are treated with an ICI plus platinum chemotherapy, and clinicians should be alert to development of irAEs, chemotherapy toxicities, and possible unique toxicities due to the combination. In patients receiving combination therapy, it is crucial to determine the cause of observed toxicity to ensure proper management without undermining treatment effect.15,17

Immune-Mediated Endocrinopathies

Endocrinopathies are among the most challenging of irAEs, due to the difficulty of making a correct diagnosis based on often nonspecific symptoms.15 Endocrine irAEs are reported in about 10% of patients treated with ICIs; hypothyroidism was reported in 6.5% to 7.9% of patients treated with nivolumab or pembrolizumab in a large meta-analysis.22 As such, it is crucial to counsel patients to inform their care team immediately if they experience symptoms such as fatigue, sluggishness, anorexia, unexplained weight loss or gain, irritability, palpitations, temperature irregularities, visual disturbances, headaches, or change in sexual drive. Not all such symptoms will indicate an immune-related reaction, but all should be investigated.15,17 For example, fatigue is the most frequently reported side effect with nivolumab or pembrolizumab, but only a small percentage is related to hypothyroidism.23

To mitigate irAEs, clinicians can anticipate and monitor for their occurrence and ensure early diagnosis and management. Tests for thyroid stimulating hormone and free T4 are recommended every 4 to 6 weeks while on treatment to identify primary hypo- or hyperthyroidism. Screening and monitoring for primary adrenal insufficiency includes cortisol levels, morning adrenocorticotropic hormone (ACTH) (if available), and basic metabolic panels at regular intervals. A standard-dose ACTH panel can help clarify indeterminate results. A precipitating cause should be identified—for example, infection rather than treatment—and adrenal CT is recommended for suspected metastasis or hemorrhage.15,19,23

ASCO recommended management of immune-mediated thyroid disorder includes an endocrinology consult, thyroid replacement (for hypothyroid) or medical treatment (for hyperthyroid). Endocrinology consultation is appropriate for any grade of immune-mediated endocrinopathy.15,19 Crucially, and distinct from other irAEs, steroids are not used to manage immune-mediated thyroid dysfunction. Table 4 summarizes management of primary hypothyroidism by grade.15,19

Grade 1 or 2 adrenal insufficiency may require holding treatment until symptom resolution and management with hydrocortisone and appropriate hormone replacement therapy (HRT) if symptomatic. For grade 3 or 4, the ICI must be held until the patient is stabilized on HRT. Some may require inpatient management to administer a stress dose of intravenous steroids. Management of asymptomatic hypophysitis includes holding the ICI, evaluating pituitary function, and initiating appropriate HRT. Patients with symptomatic hypophysitis must discontinue ICI treatment, have pituitary evaluation, and receive 1 mg/kg/day of prednisone and HRT.15,19,23  

Table 4: Guide to Managing Immune-Related Primary Hypothyroidism15,19 

 

Expert Insights From Dr Maron: Monitoring for immune-mediated hypothyroidism

 

 

Recommended  baseline assessments prior to ICI therapy and monitoring during and after treatment with ICIs are shown in Table 517 and Table 614,17The key part of the pretreatment history is determining whether the patient has a history of autoimmune disease, because the presence of most autoimmune diseases.14

 

Table 5: Recommended Baseline Assessments Prior to ICI Therapy17

 

Table 6: On- and Post-Treatment Monitoring for ICI Therapy14,17

In summary, when managing patients with advanced GC who are being treated with ICIs, it is important to maintain low threshold for systemic steroids if reaction is concerning—unless immune-mediated thyroid dysfunction is suspected. Patients must be educated about toxicities of their treatment, and to contact the oncology team if any symptoms develop, if they are admitted to hospital, or if they begin any new medications. There are many available resources about irAE management for NPs and PAs, including guidelines from ASCO, NCCN, the European Society for Medical Oncology, and the Multinational Association of Supportive Care in Cancer.14,15,20,23

Which of the following treatment regimens is a currently preferred second-line option for patients with HER2-negative advanced GC?

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